There are several Gram-positive species that cause diseases in human. The most common organisms include Staphylococcus, Streptococcus, Enterococcus, Clostridium, Bacillus, Corynebacterium, and Listeria species. Infections with common Gram-positive organisms have become more problematic to treat because of the growing trend of antibiotics drug-resistance.
Examples of such difficult-to-treat resistant bacteria include methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus (VRE).
Staphylococcus aureus can cause a range of illnesses such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome and sepsis. S. aureus is one of the most common causes of hospital-acquired infections. Streptococcus pneumoniae can cause many types of infections such as community acquired pneumonia, bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, bacteremia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess. Enterococcus can cause urinary tract infections, bacteremia, endocarditis, diverticulitis, and meningitis.
Clostridium difficile infection (CDI) is another problematic Gram-positive bacterial infection. CDI-related death has increased due to the spread of a hyper virulent NAP1/027 strain. Current treatments lead to more than 23% recurrence and have limitations against this virulent strain.
Haemophilus influenzae, a gram negative bacteria, can cause many kinds of infections including, but not limited to, ear infections, bacteremia, community-acquired respiratory infections, pneumonia and acute bacterial meningitis.
Treatment of bacterial infectious diseases is becoming more difficult and expensive due to developing resistance to existing antibiotics, spreading hypervirulent strains, and non-availability of more effacacious novel antibacterial agents.
In view of the above facts, the inventors of the present invention have realized that there should be a novel class of antibacterial agent having novel mechanism of action. After an exhaustive research, the inventors of the present invention have discovered novel compounds targeting the DNA gyrase GyrB subunit and/or topoisomerase IV ParE subunit, and hence are ready to meet the requirements of millions of patients worldwide.
In developing antibiotics having a novel mechanism of action, synthetic inhibitors targeting the DNA gyrase GyrB subunit are known in the art. For example, WO 2005/026149, WO 2006/087543, WO 2006/087544, WO 2006/087548, WO 2006/092599, WO 2006/092608, WO 2008/152418, WO 2008/020222, WO 2008/020227, WO 2008/020229, WO 2010/013222, WO 2010/067123, and WO 2010/067125 describe pyrrole derivatives having antibacterial activity. WO 2007/071965 describes bicyclic heteroaromatic compounds. WO 2014/57415 describes quinoline based compounds. These compounds had the problems of insufficient activity, low water solubility and toxicity. In addition, none of the cited references disclosed imidazole derivatives.
WO 2009/084614, incorporated herein by reference in its entirety, describes imidazole derivatives. The compounds disclosed in WO 2009/084614 have good properties, for example, sufficient in vitro antibacterial activity and no cytotoxicity. However, compound No. 150 having a thiadiazole substituent had a problem of not being efficacious in animal infection models, hence not suitable for use in human.
Compound No. 150 (WO 2009/084614)
In addition, the solubility is low compared to compounds disclosed hereinafter in this patent application for oral absorption.
Surprisingly, the hydroxyalkyl thiadiazole compounds of the present invention showed not only sufficient in vitro antibacterial activity, no cytotoxicity, good water solubility for oral absorption, but also remarkably good efficacy and safety, and hence are suitable for use in human.
Thus, the present invention provides great hope for a new antibiotic to meet the challenges of a serious global health concern due to problematic bacteria thereof causing bacterial infections, for example, but not limited to, community-acquired respiratory infections, hospital-acquired infections, urinary tract infections, and Clostridium difficile infections.